Project Summary My long-term career goal is to become an independent translational neuroscientist with expertise in dementia associated with neurodegenerative disease. This proposal is the first step in attaining this goal by combining a comprehensive training plan with an innovative program of research to investigate early anatomic markers and genetic risk factors for the progression of amyotrophic lateral sclerosis (ALS) to include frontotemporal degeneration (ALS-FTD). An estimated 50% of ALS patients develop impairments in executive function, personal and social behavior, and receptive and expressive language indicative of frontal and temporal lobe neurodegeneration, and 10% of these individuals develop dementing impairments consistent with ALS-FTD. ALS is a fatal neuromuscular disease, and ALS-FTD is consistently associated with significantly reduced time of survival. End-stages of ALS implicate eventual frontal and temporal lobe disease, and causal pathogenic mutations linking ALS and FTD have been identified; however, early indicators of ALS-FTD in patients with sporadic (i.e. non-mutation) forms of disease are lacking. To identify early markers and risk factors for the progression of ALS to ALS-FTD, I employ a series of advanced bioinformatics analyses of multimodal neuroimaging, clinical, and genetic data from a large, well-characterized ALS patient cohort. I propose two Aims: Aim 1) Identify early anatomic markers for progression from ALS to ALS-FTD by relating early, whole- brain structural magnetic resonance imaging (sMRI) to decline on targeted assessments of cognition and behavior, and Aim 2) Evaluate genetic risk factors for ALS-FTD in patients with sporadic disease by investigating the neuroanatomic and neuropsychological profiles associated with risk alleles at 18 common single nucleotide polymorphisms (SNPs) associated with ALS and FTD. I hypothesize that early frontal and temporal neurodegeneration will serve as a sensitive in vivo marker for the progression from ALS to ALS-FTD, and further hypothesize that this will by modified by SNPs that selectively confer risk for frontal and temporal lobe neurodegeneration. My proposed research is innovative in several ways: 1) I focus on the identification of early in vivo markers and risk factors for ALS-FTD, 2) I study patients with sporadic forms of disease, which accounts for 90-95% of ALS, 3) I investigate complex, multivariate relationships between regional neurodegeneration, genotype, and clinical symptoms in a comprehensive, network-based approach to the study of dementia, and 4) I take a unique clinical neuroscience approach by recruiting patients from specialized ALS and cognitive neurology clinics to minimize attainment bias. The knowledge gained from this project can be used to define patient endophenotypes, design and stratify clinical trials, and identify therapeutic targets, and also can be used in clinical settings to contribute to early identification, prognostication, and targeted treatment. Furthermore, project outcomes will increase our growing understanding of how dementia evolves in Alzheimer's Disease and related neurodegenerative diseases.